DE2107458A1 - Process for the preparation of 7 (R) Mercapto 7 deoxylincomycins - Google Patents

Description

DR. JUR. ^ ..-- THSM-WALTER BEIL

alfruü ho - .. · *. *;.:;

DR. Juss. Z ^. ..:.: a. H.-J. WOLPF eat. Feb 1971

DR. JUR. HA.iS C.ii. B £ iL. ^{ö <} '

FRANKFUSTAM MAIN - HIGH?

AOaONSTRASSESa

Our Mr. 16 963

The Upjohn Company
Kalamazoo, Mich., V.St.A.

Process for the preparation of 7 (R) -mercapto ~ 7-deoxylincomycins

Addendum to patent (patent application

P 19 20 542. 6)

In the patent (patent application P 19 20 542.6) is

a process for the preparation of T-mercapto-T-deoxylincomycins the general formula

CH ₅

0
If

SH

OH

described, which is characterized in that either a compound of the general formula

209808/1872

R.-C-HH

CH,

Hal

II

heated with water in dimethylformamide, or a compound of the general formula

III

in an inert solvent under hydrogen sulfide pressure to give a compound of the general formula

209808/1872

^fa 3

HH,

IV

and this is converted into a compound of the general formula I by acylation. During the erate procedure predominantly to compounds of the 7 (R) or D-erythro configuration leads, the second method provides predominantly connections with the opposite, i.e. the 7 (S) - or L-threo configuration

HS

.-C

4 Il

CH,

7 (R)

R.-C-HH 4 it

CH

SH

7 (S)

In the structural formulas above, R denotes an alkyl radical with no more than 20 and preferably no more ala 8 carbon atoms, a cycloalkyl radical with no more than 8 carbon atoms or an aralkyl radical with no more than 12 carbon atoms, R.-C- is the acyl part of lincomycin and shark.

0
tet bromine, chlorine or iodine.

209 808/1872

21Q7458

Eb has now been found that compounds with the 7 (R) configuration also obtained when a compound of the general formula

HF '

"CH,

used.

The process according to the invention can be carried out by the following reaction scheme be reproduced.

Shark

H
—CH,

Ilia

2 09808/1872

nt

R ₄ -G-HH

HS

Η0 / Γ- \

ψ)

> 'SR

GIL

- O

OH

In this, R., R.-C- and Hal have already indicated above

O
bene meaning.

Some or all of the HO-G groups in the 2-, 3- and 4-positions and the SH group can be esterified or etherified during the reactions, as is explained in more detail in the main patent.

Examples of alkyl radicals with not more than 20 carbon atoms are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl * Tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl ^ Nonadecyl and eicosyl radicals and their isomers. Examples for cycloalkyl radicals are the cyclopropyl, cyclobutyl, Gyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 2-methylcyclopentyl, 2,3-dimethylcyclobutyl-, 4-methylcyclobutyl- and the 3-cyclopentylpropyl radical. Examples of aralkyl radicals are the benzyl, phenethyl, a-phenylpropyl and the a-iiaphi ^ oil methyl residue.

The halogen compounds used as starting materials in the process according to the invention are described in the USA patent 3 502 648.

209808/1872

According to the invention, they become a hydrogen halide elimination subjected, suitably by heating in a solvent in the presence of an acid acceptor. Suitable acid acceptors are anhydrous sodium carbonate, potassium carbonate, triethylamine, collidine and potassium hydroxide. Suitable solvents are dimethylformamide, dimethyl sulfoxide, ethylene glycol, Benzene and alcohol. The temperature can be about 25 ° C to about the boiling point of the solvent.

The new compounds of the general formula IHa obtained are in an inert solvent under hydrogen sulfide pressure heated. They are preferably mixed with 2-propanol or a similar solvent, the one with hydrogen sulfide is saturated, and heated in a bomb to a temperature of about 100 ° 0. Higher or lower Temperatures from about 25 to about 150 ° C can also be used.

The intermediate products of the formula IHa are protonated or non-protonated depending on the prevailing pH Shape before. In protonated form they form acid addition salts, and in non-protonated form they lie as free base before. The free bases can be neutralized with a suitable acid to a pH of below about 7.0, preferably to a pH of about 2 to 6, can be converted into persistent acid addition salts. Suitable acids for this purpose are hydrochloric acid, sulfuric acid, phosphoric acid, thiocyanic acid, fluosilicic acid, hexafluoroarsenic acid, Hexafluorophosphoric acid, acetic acid, succinic acid, Citric acid, lactic acid, maleic acid, fumaric acid, pamoic acid, cholic acid, palmitic acid, mucic acid, Camphoric acid, glutaric acid, glycolic acid, phthalic acid, Y / monoic acid, Lauric acid, stearic acid, salicylic acid, 3-phenylsalicylic acid, 5-phenylsalicylic acid, 3-methylglutaric acid, o-sulfobenzoic acid, cyclopentane propionic acid, 1,2-cyclohexane

209808/1872

. dlcarbonsäure, ^ -Cyclohexanearbonsäure, Oetadecenylbernsteinsäure, QctenyTbernsteinsäure, methane, benzene, Helianthinsäure, Reinecke ¹ S acid "dimethyldithiocarbamic, Cyclohexylsulphamic, Hexadecylsulfaminsäure, Octadecylsulfaminsäure, sorbic acid, Monochloreasigsäure, ündeeylensäure, ^ -Hydroxyazobenzol - ^ - sulfonic acid, Octyldecylschwefelsäure, picric acid, benzoic acid, Cinnamic acid and similar acids.

The acid addition salts can be used for the same purposes as the free base or to purify the | free base. For example, you can convert the free base into an insoluble sais as the picrate, which then Reinigungsrerfahren can be subjected, for example, solvent extraction and washing treatments, a chromatograph! · Fractionated liquid-liquid extraction and crystallization and then to regenerate the free BaBe by treatment with alkali or used / can for conversion into another salt by metathesis. The free base can also be converted into a water-soluble salt, for example the hydrochloride or sulfate, and the aqueous solution of the salt can be extracted with various water-immiscible solvents before the free base is regenerated by treating the extracted acidic solution or by metathesis converts to another salt. The free bases of the general formula UIa can be used as buffer substances or as anti-acids. They also react with isocyanates to form urethanes and can be used to modify polyurethane resins. The acid addition salt with ihiocyanic acid, when condensed with formaldehyde, gives resinous materials which are useful as pickling inhibitors according to U.S. Patents 2,425,320 and 2,606,155. The free bases are also good carriers for toxic acids. For example, the acid addition salts with fluosilicic acid are used as moth protection

209808/1872

agents according to US Patents 1,915,334 and 2,075,359 can be used, and the acid addition salts with hexafluoroarsenic acid and hexafluorophosphoric acid are useful as pesticides U.S. Patents 3,122,536 and 3,122,552.

The following example explains the method according to the invention.

example
7 (R) -Mercapto-7-deoxylincomycin hydrochloride

209808/1872

a) Metliyl-6,7 (S) -a2; iridino-7-deoxy-a-thiolincosaminide

OH

Cl

■ OIL

SMe

52.5 g of chlorine were poured into a cooled solution of 197 »2 g Triphenylphosphine passed in 1.5 1 anhydrous acetonitrile. 18.7 g of methyl a-thiolincosaminide were added to this solution (Example 1 of U.S. Patent 3,179,565). The mixture was stirred for 2 1/2 hours at room temperature. Then 50 ml of methanol were added. The solution was taking Evaporated in vacuo. The residue was dissolved in methylene chloride dissolved and washed three times with water. The aqueous extract was made alkaline with aqueous sodium hydroxide, the sodium hydroxide solution containing ice, and extracted four times with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was filtered over silica gel chromatographed, using a mixture of chloroform and methanol in the ratio for the elution 4: 1 used and 100 ml fractions collected. The effluent was checked by thin layer chromatography, and the fractions were collected on this basis. 4.4 g of material were obtained, consisting essentially of methyl-7 (S) -chloro-7-deoxy-a-thiolincosaminide consisted of about 3.2 g of a fraction containing this product and a slightly stronger one contained polar product. The last-mentioned fraction gave, on trituration with methanol, 2.48 g of methyl-7 (S) -chlor-

209808/1872

7-deoxy-a-thiolincosaminide. The methanol solution was evaporated to dryness and the residue was chromatographed again over silica gel. 700 mg was obtained methyl-6,7 (S) -aziridino-7-deoxy-a-thiolincosaminid (slightly more polar than methyl-7 (S) -chloro ⁱ -7-deoxy-a-thiolincosaniinid), which in the Crystallization from methanol gave 230 mg of crystals with the following properties: Έ = 186-189 ° C

. = 281 ° (methyl sulfoxide)

Analysis calculated for CgH ^

C 45.94 | H 7.28} Ή 5.95} S 13.63; found: 0 45.85} H 7.24} N 6.28} Cl 0

b) methyl-7 (R) -mercapto-7-aesoxy-a-thiolincosaminide

CH,

SMe

A mixture of 1.5 g of methyl £, 7 (S) -aziridino-7-deoxya-thiolincosaminide in 30 ml of 2-propanol was saturated with hydrogen sulfide while cooling in an ice-methanol bath. The reaction mixture was heated in a bomb on a steam bath for 5 hours. During this time, that broke up Methyl 6,7-aziridino-7-deoxy-a-thioilcosaminide slow. Then began. 7 (R) -mercapto-7-deoxy-a-thiolincosaminide the solution to fail. When filtering the cooled mii-

209808/18 7-2

1.6 g of product were obtained.

c) T (R) mercapto-7-deoxylincomycin hydrochloride

The acylation of methyl-7 (R) -mercapto-7-deoxy-erthiolin cosaminide with trans-1-methyl-4-n-propyl-L-proline gives 7 (R) -mercapto-7-deoxyrincomycin hydrochloride the formula given above.
°

= 125 ° (H ₂ O)
Analysis; calculated for

C 51.15? H 8.111 Ή 6.63l found: C 51.18; H 8.16; N 6.96

209808/1872

Claims (4)

Claims 1. Process for the preparation of 7 (R) -mercapto-7-deoxylincomycins the general formula CH, HS in which R is an alkyl radical with not more than 20 carbon atoms and preferably with not more than 8 carbon atoms, a Cycloalkyl radical with not more than 8 carbon atoms or an aralkyl radical with not more than 12 carbon atoms and R.-C- is the acyl part of Μηοοπψοίη, according to patent 0 (Patent application P 19 20 54-2. 6), characterized in that one Solution of a compound of the general formula 209808/1872 CfI, Hal IH, \ qh J > 's OH in which Hal is chlorine, bromine or iodine and R is as given above Has meaning, heated in the presence of a hydrogen halide, the compound obtained general formula SR heated in an inert solvent under hydrogen sulfide pressure and the resulting compound of the general formula 209808/1872 -H- CH, HS acylated. 2. The method according to claim 1, characterized in that the hydrogen halide acceptor is anhydrous sodium carbonate used. 3. Compound of the general formula in which R has the meaning given above, 209808/1872 4. A compound according to claim 3, in which R is the methyl or Ethyl radical is For The Upjohn Company Kalamazoo, Mich., V.St.A. Lawyer 209808/1872